E2F4 Promotes Neuronal Regeneration and Functional Recovery after Spinal Cord Injury in Zebrafish.

Shota Sasagawa,Shiko Okabe,Soichiro Murakami,Yuka Hayakawa,Yoshifumi Ashikawa,Reiko Kawase,Koki Kawaguchi,Yuhei Nishimura,Mizuki Yuge,Toshio Tanaka

doi:10.3389/fphar.2016.00119

Abstract

Mammals exhibit poor recovery after spinal cord injury (SCI), whereas non-mammalian vertebrates exhibit significant spontaneous recovery after SCI. The mechanisms underlying this difference have not been fully elucidated; therefore, the purpose of this study was to investigate these mechanisms. Using comparative transcriptome analysis, we demonstrated that genes related to cell cycle were significantly enriched in the genes specifically dysregulated in zebrafish SCI. Most of the cell cycle-related genes dysregulated in zebrafish SCI were down-regulated, possibly through activation of e2f4. Using a larval zebrafish model of SCI, we demonstrated that the recovery of locomotive function and neuronal regeneration after SCI were significantly inhibited in zebrafish treated with an E2F4 inhibitor. These results suggest that activation of e2f4 after SCI may be responsible, at least in part, for the significant recovery in zebrafish. This provides novel insight into the lack of recovery after SCI in mammals and informs potential therapeutic strategies.

Highlights

Spinal cord injury (SCI) in mammals typically results in permanent neurological deficits, whereas regenerative organisms, such as amphibians and fish, are capable of regeneration after SCI
We demonstrated that e2f4, tfdp1, and foxm1 possibly regulate zebrafish SCI-specific differentially expressed genes (DEGs)
When cells leave G0 and enter into the cell cycle, RBL2 dissociates from E2F4 and the MuvB core resulting in the release of the DREAM complex from the promoters of genes related to the cell cycle (Sadasivam and DeCaprio, 2013)

Summary

Introduction

Spinal cord injury (SCI) in mammals typically results in permanent neurological deficits, whereas regenerative organisms, such as amphibians and fish, are capable of regeneration after SCI (reviewed in Lee-Liu et al, 2013; Vajn et al, 2013; Silver et al, 2015). After SCI in mammals astrocytes form a glial scar and secrete extracellular matrix (ECM) components such as chondroitin sulfate and proteoglycans. These extrinsic mechanisms can cause a relative lack of growth-promoting molecules and/or a surplus of growth-inhibitory molecules, Abbreviations: SCI, Spinal cord injury; ECM, extracellular matrix; DEGs, differentially expressed genes; TFs, transcription factors; DREAM complex, TFDP1, RBL2, E2F4, and the MuvB core complex; dpi, days-post-injury; dpf, days-postfertilization. A comprehensive understanding of the mechanisms underlying the difference between non-regenerative and regenerative organisms is still required

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